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Is Interleukin-10 a "10" in Virus-Provoked Asthma?

Posted on: Thursday, 25 August 2005, 03:00 CDT

In both children and adults, asthma exacerbations are caused primarily by viral respiratory infections, with rhinovirus being the most common infectious organism detected (1, 2). In contrast to the pathophysiology of allergen-provoked asthma, there are significant differences with asthma attacks associated with respiratory infections. First, the neutrophil, rather than the eosinophil, is the predominant inflammatory cell in virus-associated asthma exacerbations (3, 4). This differential in cellular inflammation is curious because sputum eosinophils often increase before the exacerbation is clinically manifest (5). Second, bronchodilation by β-agonists is attenuated in virus-induced asthma, limiting the effectiveness of this intervention (6). Finally, inhaled corticosteroids, which are effective in asthma control, are less beneficial either to prevent or reverse exacerbations caused by respiratory infection (7).

In this issue of the AJRCCM (pp. 433-439), Grissell and colleagues (8) present new information that identifies potentially important immunomechanisms by which viral respiratory infections may cause severe episodes of asthma. Fifty-nine patients hospitalized for acute asthma were recruited, and 46 had respiratory virus recovered at admission. An induced sputum sample was collected and analyzed for selected cytokines and chemokines, as well as viral identification. Importantly, the investigators included critical comparative groups to define more fully the role of respiratory viruses in stimulating a specific inflammatory response that produced the asthma exacerbation. These carefully selected groups allowed for controlled observations into the effects of the virus alone in normal subjects, patients with persistent asthma but no infection, and patients with acute asthma either with or without a viral respiratory infection.

Grissell and colleagues (8) detected respiratory viruses in nearly 80% of patients with acute asthma and symptoms of a respiratory infection, as well as in a normal control population with cold symptoms; rhinoviruses were detected most often in both of these groups. Therefore, the microbiological pattern of infectious viruses in this study paralleled observations noted by others (1, 2). Two patterns of response were seen: rhinovirus respiratory infections in the normal control and acute asthma group were associated with sputum neutrophilia, whereas sputum eosinophils were increased only in patients with persistent but stable asthma. Thus, neutrophilia did not differentiate between the response to virus in a control population or in patients with asthma with an exacerbation during the acute infection. This observation suggests that factors other than, or more likely in addition to, neutrophils are necessary for an asthma exacerbation to occur with a respiratory virus infection.

Airway inflammation in virus-provoked asthma involves the generation of interferons, chemokines, cytokines, and other mediators rather than direct airway injury by the noncytopathic rhinovirus. Grissell and colleagues (8) chose to measure mRNA of several factors that regulate neutrophilic and eosinophilic inflammation. Among the factors that were measured, regulated on activation, normal T-cell expressed and secreted (RANTES) mRNA was elevated by viral infection whether or not there was an accompanying asthma exacerbation. The one measured cytokine gene product that appeared to change uniquely in patients with acute asthma with a respiratory infection was interleukin (IL)-10. These observations suggest that the generation of IL-10 is a differentiating factor and is somehow associated with the provocation of acute asthma during a cold. During the recovery phase, sputum IL-10 mRNA and neutrophils returned to normal levels, but at this stage, eosinophils increased and paralleled the usual pattern of inflammation seen in asthma.

As noted (8), IL-10 is produced by a wide variety of cells, macrophages, monocytes, dendritic cells, natural killer cells, epithelial cells, and T cells. The authors speculate that IL-10 reduces eosinophilic responses during the acute infection, but may increase airway hyperresponsiveness. Although airway responsiveness was not measured in these subjects, the authors' proposed scenario fits nicely with their data, and focuses our attention on IL-10 as a key, and perhaps differentiating, cytokine to explain the linkage between a viral respiratory infection and the provocation of an asthma exacerbation. The identification of IL-10 as a "causative" mediator in virus-provoked asthma is a bit of a surprise. In general, IL-10 tends to be an immunoregulatory cytokine and its generation is usually associated with resolution of the inflammatory process (9). For example, IL-10 is secreted by regulatory T cells, and transfer of IL-10-producing cells can block allergic inflammation in animal models (10, 11). Perhaps in virus-provoked asthma, as suggested by the authors (8), IL-10 has different and unique actions. Alternately, it is possible that the increased IL- 10 is not playing a causal role, but is instead a response to a greater degree of airway inflammation in individuals predisposed to virus-induced exacerbations. These possibilities await further study.

The observations of Grissell and colleagues (8) point to IL-10 as an indicator of rhinovirus-provoked asthma, both in children and adults. This, by itself, is a major step forward in identifying the key players in virus-provoked asthma. Many additional pieces, such as the following, need to be placed in this puzzle to more fully understand how respiratory viruses induce an asthma exacerbation: (1) host susceptibility factors (12, 13), (2) mechanisms of the acute and often unresponsive airflow obstruction, and (3) effective treatment for both intervention and prevention. The observations by Grissell and coworkers add critical new information as we try to understand the mystery of how an innocuous respiratory infection, like the common cold produced by rhinoviruses, can have such devastating effects in some patients with asthma.

Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

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9. Hawrylowicz CM, O'Garra A. Potential role of interleukin-10- secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 2005;5:271-283.

10. Stampfli MR, Cwiartka M, Gajewska BU, Alvarez D, Ritz SA, Inman MD, Xing Z, Jordana M. Interleukin-10 gene transfer to the airway regulates allergic mucosal sensitization in mice. Am J Respir Cell Mol Biol 1999;21:586-596.

11. Oh JW, Seroogy CM, Meyer EH, Akbari O, Berry G, Fathman CG, Dekruyff RH, Umetsu DT. CD4 T-helper cells engineered to produce IL- 10 prevent allergen-induced airway hyperreactivity and inflammation. J Allergy Clin Immunol 2002;110:460-468.

12. Mckean MC, Hewitt C, Lambert PC, Myint S, Silverman M. An adult model of exclusive viral wheeze: inflammation in the upper and lower respiratory tracts. Clin Exp Allergy 2003;33:912-920.

13. Gern JE, Busse WW. Relationship of viral infections to wheezing illnesses and asthma. Nat Rev Immunol 2002;2:132-138.

DOI : 10.1164/rccm.2506005

WILLIAM W. BUSSE, M.D.

JAMES E. GERN, M.D.

University of Wisconsin

Madison, Wisconsin

Copyright American Thoracic Society Aug 15, 2005

Source: American Journal of Respiratory and Critical Care Medicine

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